WO1997018194A1

WO1997018194A1 - CYCLIC AND HETEROCYCLIC N-SUBSTITUTED α-IMINOHYDROXAMIC AND CARBOXYLIC ACIDS

Info

Publication number: WO1997018194A1
Application number: PCT/EP1996/004776
Authority: WO
Inventors: Werner Thorwart; Wilfried Schwab; Manfred Schudok; Burkhard Haase; Eckart Bartnik; Klaus-Ulrich Weithmann
Original assignee: Hoechst Aktiengesellschaft
Priority date: 1995-11-13
Filing date: 1996-11-04
Publication date: 1997-05-22
Also published as: RU2164914C2; BR9611479A; HUP9903405A1; US20010011134A1; CN1202156A; KR19990067685A; CN1131215C; CZ297550B6; EP0861236B2; DK0861236T3; EP0861236B1; HU223086B1; HUP9903405A3; AU7562496A; JP2000500145A; ES2170884T5; EP0861236A1; TR199800849T2; BR9611479B1; MX9803753A

Abstract

Compounds of formula (I) are suitable for use in the production of medicaments used for treating disorders associated with increased activity of matrix-degrading metalloproteinases.

Description

description

Cyclic and heterocyclic N-substituted α-iminohydroxamic and carboxylic acids

The invention relates to cyclic and heterocyclic N-substituted α-iminohydroxamic and carboxylic acids, processes for their preparation and

Use same as a medicine.

EP 0 606 046 describes some arylsulfonamido-hydroxamic acid derivatives and their action as matrix metalloproteinase inhibitors.

In pursuit of more effective compounds for the treatment of

To find connective tissue diseases, it has now been found that the

Iminohydroxamic acid derivatives inhibitors of

Metalloproteinases are.

The invention relates to a compound of formula I.

and / or an optionally stereoisomeric form of the compound of the formula I and / or a physiologically tolerable salt of the compound of the formula 1, where in the case i) R ^{1 is} a) a radical of formula II

b) a radical of the formula III

c) a radical of the formula IV

wherein Z is a residue of a heterocycle or substituted heterocycle, such as

1) pyrrole,

2) thiazole,

3) pyrazole,

4) pyridine

5) imidazole,

6) pyrrolidine,

7) piperidine,

8) thiophene,

9) oxazole,

10) isoxazole,

1 1) Morpholine or

1 2) piperazine, d) naphthyl,

e) naphthyl, mono- or trisubstituted by R ² , or f) a radical of the formula V.

where o is the number 1 or 2, and one of the carbon atoms in the ring is optionally replaced by -O- or -S-, and

Q as part of structural formula I.

1) for structural part VI

2) the structural part VII

3) for structural part VIII

4) the structural part IX

or

5) for the structural part X

where D is NR or S,

R ² for

1) phenyl or

2) Phenyl mono- to trisubstituted by

2.1 hydroxy,

2.2 -OR ¹⁰ where R ¹⁰

1) (C ₁ -C ₆ ) alkyl,

2) (C ₃ -C ₆ ) cycloalkyl,

3} benzyl or

4) phenyl means

2.3 -COOH,

2.4 (C ₁ -C ₆ ) alkyl,

2.5 (C3-C ₆ ) cycloalkyl-O- (C ₁ -C ₄ ) alkyl,

2.6 halogen,

2.7 -CN,

2.8 -NO ₂ ,

2.9 -CF ₃ ,

2.10 -OC (O) -R ¹⁰ and R ¹⁰ as defined above,

2.1 1 -OC (O) -phenyl, mono- or disubstituted by R ³ , 2.1 2 -C (O) -OR ¹⁰ and R ¹⁰ as defined above,

2.1 3 methylenedioxo,

2.14 -C (O) -NR ^{1 1} R ^{1 2} , wherein

R ^{1 1} and R ^{1 2 may be the} same or different and

1) hydrogen atom,

2) (C ₁ -C ₄ ) alkyl or

3) benzyl means or

4) together with the N atom to which they are attached a pyrrolidine, piperidine, morpholine or

Form piperazine residue, or

2.1 5 -NR ¹³ R ^{1 4} , wherein

R ^{13 represents} hydrogen atom or (C ₁ -C ₄ ) alkyl and wherein

R ¹⁴ 1) hydrogen atom,

2) (C ₁ -C ₄ ) alkyl,

3) benzyl,

4) -C (O) -R ¹⁰ or

5) -C (O) -OR ¹⁰ means

R ³ and R ^{4 are the} same or different and

1) hydrogen atom,

2) (C ₁ -C ₅ ) alkyl,

3) (C ₁ -C ₅ ) alkoxy,

4) halogen,

5) hydroxy,

6) -OC (O) -R ¹⁰ and R ¹⁰ as defined above mean, or

7) R ³ and R ⁴ together form the radical -O-CH ₂ -O-,

R ⁵ for

a) hydrogen atom,

b) (C ₁ -C ₅ ) alkyl or

c) benzyl, and R ⁶ , R ⁷ and R ^{8 are the} same or different and are for

a) hydrogen atom, or

b) have the meaning for case i) of R ² under points 2.1 to 2.14, and

n stands for zero, 1 or 2,

m stands for zero, 1 or 2, the sum of n and m being 1, 2 or 3, or for the case ii)

R ¹ for

1) phenyl or

2) phenyl, mono- to trisubstituted by R ² , where R ^{2 is} as defined for the case i) under points 2.1 to 2.15,

Q stands for the structural part X and

R ⁶ , R ⁷ and R ^{8 are the} same or different and are as defined above, n is 1 and

m denotes 1, or where in the case iii)

R ¹ , Q, R ⁶ , R ⁷ and R ^{8 are the} same or different and are suitable for the case ii)

have the meaning given,

m and n are zero, 1 or 2 and the meaning of n and m is not the same, and

X for

a) a covalent bond,

b) -O-,

c) -S-,

d) -S (O) -,

e) -S (O) ₂ -,

f) -C (O) - or

g) -C (OH) - stands, and Y for

a) -O- or

b) -S- stands, and

A stands for HO-NH-C (O) - or HO-C (O) - and

B for a) - (C _H2 ) _q -, where q is zero, 1, 2, 3 or 4, or

b) -CH = CH- stands.

Preferred is a compound of formula I and / or a physiologically acceptable salt of the compound of formula I and / or an optionally stereosiomeric form of the compound of formula I, wherein

R ¹ in the case i) represents a radical of the formula II or III and Q represents the

Structural part VI, VII, VIII or X stands,

R ¹ for case ii) for phenyl or phenyl, mono- to trisubstituted by

Methoxy, and Q stands for structural part X, or R ¹ for case iii) for phenyl, Q stands for structural part X, and n is zero and m

2 means and

A stands for HO-NH-C (O) - or HO-C (O) -,

B represents a covalent bond,

X represents oxygen atom or a covalent bond, and

R ² for phenyl or phenyl substituted by

a) hydroxy,

b) -OR ¹⁰ , in which R ^{1 is 0} (C ₁ -C ₃ ) -alkyl or benzyl, c) (C ₁ -C ₂ ) -alkyl,

d) fluorine or chlorine,

e) -CN,

f) -CF ₃ or

g) NR ^{1 3} R ¹⁴ , in which R ^{1 3} and R ^{14 are} (C ₁ -C ₃ ) -alkyl, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are the} same or different and are for

a) hydrogen atom,

b) methoxy,

c) methylenedioxo,

d) amino or

e) Hydroxy stand.

The compounds are particularly preferred

R-2- (biphenylsulfonyl) -1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,

R-2- (4-chloro-biphenylsulfonyl) -1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,

R-2- (4-chloro-biphenylsulfonyl) -1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

R-2- (4-phenoxybenzenesulfonyl) -1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,

R-2- (4-phenoxybenzenesulfonyl) -1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

R-2- (4- (4-dimethylaminophenoxy) benzenesulfonyl) -1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,

R-2- (4-dimethylaminobiphenylsulfonyl) - 1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

R-2- (4-benzoylphenylsulfonyl) -1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,

R-2- (4-methoxybenzenesulfonyl) -7-hydroxy-1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,

R-2- (4-methoxybenzenesulfonyl) -7-nitro-1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,

2- (4-methoxybenzenesulfonyl) -6,7-propylene-1, 2,3,4-tetrahydroisoquinoline-1-hydroxamic acid,

R-5- (4-methoxybenzenesulfonyl) -4, 5,6,7-tetrahydro-1 H -imidazo- (4,5-c) -pyridine-6-hydroxamic acid,

R-2- (4-methoxybenzenesulfonyl) -1, 2,3,4-tetrahydro-9H-pyrido- {3,4-c) indole-3-hydroxamic acid,

R-2- (4-phenoxybenzenesulfonyl) -1, 2,3,4-tetrahydro-9H-pyrido (3,4-c) indole-3-hydroxamic acid. In addition, those compounds of the formula I in which the central carbon atom between the amino and acid groups is present as an R enantiomer should be particularly emphasized.

The term halogen means fluorine, chlorine, bromine or iodine.

The term alkyl or alkoxy is understood to mean residues thereof

Carbon chain can be straight-chain, branched or cyclic. Cyclic alkyl radicals are, for example, 3- to 6-membered monocycles such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The "heterocycles of formula V" include, for example, thiomorpholine, piperidine, morpholine or piperazine.

Suitable physiologically tolerable salts of the compound of formula I are, for example, alkali, alkaline earth and ammonium salts, including those of organic ammonium bases or basic amino acids.

The invention also relates to a process for the preparation of the compound of the formula I and / or a physiologically tolerable salt of the compound of the formula I and / or an optionally stereoisomeric form of the compound of the formula I, which is characterized in that

a) an imino acid of the formula XI

wherein radicals Q, and n and m are as defined in formula I, reacted with a (C ₁ -C ₄ ) alcohol or a benzyl alcohol to give the compound of the formula XII,

wherein R _{X is} (C ₁ -C ₄ ) alkyl or benzyl, or b) a compound of the formula XII prepared by process a) with the compound of the formula XIII,

in which R ^{1 is} as defined in formula I and R _Z denotes chlorine atom, imidazolyl or --OH, in the presence of a base or optionally a dehydrating agent, to give a compound of the formula XIV,

wherein Q, R ¹ , n and m are as defined in formula I and R _χ as defined in formula XII, or c) reacting a compound of formula XII prepared by process a) with a base and then with a compound of formula XIII to a compound of formula XIV, or d) reacting a compound of formula XI with a compound of formula XIII to a compound of formula XV

wherein Q, R ¹ , n and m are as defined in formula I, or e) converting a compound of the formula XIV to a compound of the formula XV, or f) a compound of the formula XIV prepared by process b) or c) with the hydroxylamine Formula XVI,

(XVI) H ₂ N-OR _y in which R _{Y represents a} hydrogen atom or an oxygen protecting group, to give the compound of the formula I and, if appropriate, the

Splits off oxygen protecting group, or g) a compound of the formula XV prepared by process d) or e) is reacted with the hydroxylamine of the formula XVI to give the compound of the formula I, or h) a compound of the formula I prepared by the process f) or g) which occurs due to its chemical structure in enantiomeric forms, through salt formation with enantiomerically pure acids or bases,

Chromatography on chiral stationary phases or derivatization using chiral enantiomerically pure compounds such as amino acids, separation of the diastereomers thus obtained, and cleavage of the chiral ones

Separates auxiliary group into the pure enantiomers, or i) the compound of the formula I prepared by processes f), g) or h) is either isolated in free form or, if acidic or basic groups are present, converted into physiologically tolerable salts, if appropriate.

In the case of the (C ₁ -C ₄ ) alcohols, the reaction in process step a) is carried out in the presence of HCl gas or thionyl chloride under customary conditions

Reaction conditions. The corresponding benzyl esters of the formula XII are prepared in benzene or toluene with the corresponding alcohol and an acid such as p-toluenesulfonic acid. Tertiary butyl esters can be produced, for example, using isobutene and sulfuric acid by known processes.

The reaction in process step b) is carried out in the presence of a

basic compound such as N-methylmorpholine (NMM), N-ethylmorpholine (NEM), triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, collidine, imidazole or sodium carbonate in solvents such as tetrahydrofuran (THF),

Dimethylformamide (DMF), dimethytacetamide, dioxane, acetonitrile, toluene,

Chloroform or methylene chloride, or in the presence of water.

The sulfonic acid chlorides of the formula XIII are preferably used in the presence of NMM in THF.

The reaction in process step c) is carried out in the presence of a base such as KOH, LiOH or NaOH.

The reaction in process step d) is carried out in an aqueous organic solvent system, preferably in THF and water in the presence of a base such as sodium carbonate and the compound of the formula XIII. Furthermore, the reaction can be carried out without a solvent, with or without a base, under reduced pressure, as achieved by an oil pump. The saponification of the compound of formula XIV to the compound of

Formula XV (process step e) is, for example, basic, preferably acidic or, in the case of the benzyl derivatives, by hydrogenolysis. In the case of basic saponification, it is necessary to treat the carboxylic acid by treatment with another acid, e.g. dilute hydrochloric acid to release from the carboxylic acid salt.

The reaction in process step f) is carried out under the conditions customary for the formation of carboxamides in a suitable solvent, e.g. Alcohols or dimethylformamide.

In the reaction according to process step g), the carboxylic acids of the formula XV are activated. Activated carboxylic acids are, for example, acylhaiogenides, acyl azides, mixed anhydrides and carbonates. Are preferred

Acyl chloride or fluoride, mixed anhydrides and carbonates

Pivaloyl chloride, ethyl, isopropyl or isobutyl chloroformate; Active esters such as cyanoethyl, o- or p-nitrophenyl, succinimido or phthalimido, as well as those provided by the coupling reagents such as dnsopropyicarbodiimide (DIC), carbonyldiimidazole (CDI), dicyclohexylcarbodnmid (DCC) or benzotriazolyltetramethyluronium (optionally with the addition of tetrafluoroboronium, tetrafluoroboronium, tetrafluoroburonium, tetrafluoroburonate, optionally with the addition of tetrafluoroboronium, tetrafluoroboronium, tetrafluoroburonate, optionally with the addition of tetrafluoroboronium, tetrafluoroboronium, tetrafluoroburonate, with or without the addition of tetrafluoroboronium, tetrafluoroburonate, optionally with the addition of tetrafluoroburonium, tetrafluoroboronium, tetrafluoroboronium, tetrafluoroburonate), with or without the addition of tetrafluoroboronium (Tetrafluoroburonium)

Hydroxybenzotriazole (HObt) or oxohydroxybenzotriazine (HOObt), available activated carboxylic acids, with aprotic solvents being preferred as solvents

The starting products and reagents used can either be prepared by known processes or are commercially available

Suitable imino acids of the formula XI in which n and m are 1, for example 1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 1, 2,3,4-tetrahydro-9H-pyrido (3,4- b) -Indole-3-carboxylic acid or optionally 1 - or 3-substituted 4,5,6,7-tetrahydro-1 H-imidazo- (4,5-c) -pyridine-6-carboxylic acids. They are preferably prepared by Cycle the corresponding amino acids with formaldehyde in the presence of an acid, such as hydrochloric or sulfuric acid, according to the method of Pictet-Spengler (see WM Whaley, Organic Reactions 6 (1951) 151.

In the event that n is a zero and m is a 2 in the imino acid of the formula XI, 1, 2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-1-carboxylic acid and 6, 7-propylene-1, 2,3,4-tetraisoquinoline-1-carboxylic acid can be used as the starting product. To prepare the latter compound, indane is alkylated according to Friedel-Crafts with phenylsulfonylarziridine. The 4- (2-benzenesulfonamidoethyl) indane obtained is cyclized using glyoxylic acid in HBr / glacial acetic acid; the subsequent cleavage of the benzenesulfony residue with iodine / red phosphorus in HBr / glacial acetic acid.

An example of the case where n is 1 and m is zero in compound XI is indoline-2-carboxylic acid. They are produced, for example, by catalytic hydrogenation of the indole-2-carboxylic acid. The cyclization of 2-chlorophenylalanine or 2-hydroxy-3- (2-chlorophenyl) propionic acid to give imino acids of the formula XI may also be mentioned.

If compounds of the formula I allow diastereoisomeric or enantiomeric forms and are obtained as their mixtures in the chosen synthesis, the separation into the pure stereoisomers is possible either by chromatography on an optionally chiral support material, or, if the racemic compound of the formula I or a compound of the formula XI is capable of salt formation by fractional crystallization of the diastereomeric salts formed with an optically active base or acid as auxiliary. Modified silica supports (so-called Pirkle phases) and high-molecular carbohydrates such as triacetyl cellulose are suitable as chiral stationary phases for the separation of enantiomers by thin-layer or column chromatography. After appropriate derivatization known to the person skilled in the art, gas chromatographic methods on chiral are also for analytical purposes Stationary phases applicable. To separate the enantiomers of the racemic carboxylic acids, the optically active, generally commercially available bases such as (-) - nicotine, (+) - and (-) - phenylethylamine, quinine bases, L-lysine or L- and D-arginine are used to dissolve the differently soluble ones diastereomeric salts formed, the less soluble component isolated as a solid, the more soluble diastereomer separated from the mother liquor, and the pure enantiomers obtained from the diastereomeric salts thus obtained. In principle, the racemic compounds of the formula I, which contain a basic group such as an amino group, can be treated with optically active acids, such as (+) -campher-10-sulfonic acid, D- and L-tartaric acid, D- and L- Lactic acid and (+) and (-) - mandelic acid in the pure enantiomers

convict. It is also possible to use chiral compounds which contain alcohol or amine functions with correspondingly activated or optionally N-protected enantiomerically pure amino acids in the corresponding esters or amides, or conversely chiral carboxylic acids with carboxy-protected

convert enantiomerically pure amino acids into the amides or with enantiomerically pure hydroxycarboxylic acids such as lactic acid into the corresponding chiral esters. The chirality of the amino acid or alcohol residue introduced in enantiomerically pure form can then be used for the separation of the isomers by carrying out a separation of the diastereomers now present by crystallization or chromatography on suitable stationary phases and then cleaving off the chiral part of the molecule which is carried along using suitable methods.

Acidic or basic products of the compound of formula I can exist in the form of their salts or in free form. Pharmacological are preferred

compatible salts, e.g. B. alkali or alkaline earth metal salts or hydrochlorides, hydrobromides, sulfates, hemisulfates, all possible phosphates and salts of amino acids, natural bases or carboxylic acids. Hydroxylamine can be used in free form, obtainable from hydroxylamine salts and a suitable base in solution or in O-protected form or in each case also in the form of its salts. The preparation of the free hydroxylamine is known from the literature and can be carried out, for example, in alcoholic solution. Preference is given to using the hydrochloride together with alcoholates such as sodium methoxide, potassium hydroxide or potassium t-butoxide.

O-protected hydroxylamine derivatives preferably contain mild

Protective groups that can be split off under conditions. Protective groups of the silyl, benzyl and acetal type are particularly preferred here. The O-trimethylsilyl, O-tertiary-butyldimethylsilyl, O-benzyl, O-tertiary-butyl and O-tetrahydropyranyl derivatives are particularly suitable.

Starting compounds and intermediates used in the manufacture of

Compound of formula I can be used, if functional

Groups such as hydroxyl, thiol, amino or carboxyl, for example in the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ , are present in a suitably protected form

be used.

The introduction of protective groups is necessary in all cases in which a chemical reaction to other than that is desired

Reaction centers undesirable side reactions are expected

(T.W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1,991).

The protective groups used can be split off before or after the reaction of the compound of the formula XII to the compound of the formula I.

In particular, auxiliaries and bases which can be used are: HObt, HOObt, N-hydroxysuccinimide (HOSu), TEA, NMM, NEM, DIPEA, imidazole.

Preferred solvents for the reaction are: dichloromethane (DCM), THF, acetonitrile, N, N-dimethylacetamide (DMA), DMF and N-methylpyrrolidone (NMP). The preferred temperatures are between - 78 ° C and + 90 ° C, depending on the boiling temperature and the type of solvent used. The temperature range from -20 to + 30 ° C. is particularly preferred.

The production of physiologically compatible salts from compounds of the formula I capable of salt formation, including their stereoisomeric forms, is carried out in a manner known per se. The carboxylic acids and hydroxamic acids form with basic reagents such as hydroxides, carbonates, hydrogen carbonates, alcoholates and ammonia or organic bases, for example

Trimethylamine or triethylamine, ethanolamine or triethanolamine or also basic amino acids, such as lysine, ornithine or arginine, stable alkali metal, alkaline earth metal or optionally substituted ammonium salts. If the

Compounds of the formulas I having basic groups, stable acid addition salts can also be prepared with strong acids. Both inorganic and organic acids such as hydrogen chloride,

Hydrogen bromide, sulfur, phosphorus, methanesulfone, benzenesulfone, p-toluenesulfone, 4-bromobenzenesulfone, cyclohexylamido sulfone,

Trifluoromethylsulfonic, acetic, oxalic, tartaric, succinic or trifluoroacetic acid in question.

The invention also relates to pharmaceuticals, characterized by an effective content of at least one compound of the formula I and / or one

physiologically tolerable salt of the compound of formula I and / or an optionally stereoisomeric form of the compound of formula I, together with a pharmaceutically suitable and physiologically tolerable carrier, additive and / or other active substances and auxiliaries.

Due to the pharmacological properties, the

Compounds according to the invention for the prophylaxis and therapy of all such diseases, in the course of which an increased activity of matrix-degrading metalloproteinases is involved. These include degenerative Joint diseases such as osteoarthrosis, spondylosis, cartilage loss after joint trauma or extended joint immobilization after meniscus or

Patella injuries or torn ligaments. It also includes connective tissue diseases such as collagenosis, periodontal diseases, wound healing disorders and chronic musculoskeletal disorders such as inflammatory, immunological or metabolic acute and chronic arthritis, arthropathy, myalgia and disorders of bone metabolism. The compounds of formula I are also suitable for the treatment of

Ulceration, atherosclerosis and stenosis. Furthermore suppress the

Compounds of formula I significantly release the cellular tumor

Necrosis factor (TNFα) and are therefore suitable for the treatment of

Inflammation, cancer, tumor metastasis, cachexia,

Anorexia and septic shock.

The medicaments according to the invention are generally administered orally or parenterally. Rectal or transdermal application is also possible.

The invention also relates to a method for producing a medicament, which is characterized in that at least one compound of the formula I is brought into a suitable dosage form with a pharmaceutically suitable and physiologically acceptable carrier and, if appropriate, other suitable active ingredients, additives or auxiliaries.

Suitable solid or non-standard preparation forms are, for example

Granules, powders, dragees, tablets (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions as well as preparations with protracted active ingredient release, in the production of which are common auxiliaries, such as carriers, explosives, binders, coatings -, swelling agents, lubricants or lubricants, flavors, sweeteners and solubilizers are used. Magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, Milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil,

Polyethylene glycol and solvents such as sterile water and mono- or polyhydric alcohols such as glycerin called.

The pharmaceutical preparations are preferably produced and administered in dosage units, each unit containing as active ingredient a certain dose of the compound of the formula I according to the invention. In the case of solid dosage units such as tablets, capsules, dragees or suppositories, this dose can be up to about 1,000 mg, but preferably about 50 to 300 mg, and for injection solutions in ampoule form up to about 300 mg, but preferably about 10 to 100 mg.

For the treatment of an adult patient weighing approximately 70 kg, daily doses of approximately 20 mg to 1000 mg of active ingredient, preferably approximately 100 mg to 500 mg, are indicated, depending on the effectiveness of the compounds according to formula I. Under certain circumstances, however, higher or lower daily doses may also be appropriate. The administration of the daily dose can be done both by

Single administration in the form of a single dosage unit or several smaller dosage units as well as multiple administration of divided doses at certain intervals.

¹ H-NMR spectra were recorded on a 200 MHz device from Varian, usually with tetramethylsilane (TMS) as the internal standard and at room temperature (RT). The solvents used are given in each case. End products are usually determined by mass spectroscopic methods (FAB-, ESI-MS). Temperatures in degrees Celsius, RT means room temperature (22-26 ° C). Abbreviations used are either explained or correspond to the usual conventions. Manufacturing examples

Compounds 1 -1 2, 14-23, 27, 30 and 33 in Table 1 were prepared analogously to the procedures described in Examples 13, 24-26, 28, 29, 31 and 32.

In Examples 4 to 9, sulfonation was first carried out using p- (Ex. 4, 6, 9) or m- (Ex. 5,7,8) nitrobenzenesulfonyl chloride as below

"Tic sulfonation" (see Example 13). The nitro group is then hydrogenated under standard conditions which are known to the person skilled in the art, using hydrogen under atmospheric pressure and 10% Pd on activated carbon in methanol to give the amine.

In all cases it is also possible to use the tic benzyl ester described in Example 13 for the sulfonation. With the following

Hydrogenation is then carried out at the same time cleavage of the benzyl ester and reduction to the amine. The identical products p- or

m-Aminobenzenesulfonyl-Tic are then further reacted as follows:

Example 4:

Acetylene is initially carried out under standard conditions

(Triethylamine / DMAP / acetic anhydride); the one obtained in good yield

The N-acetyl compound is then reacted further to the hydroxamic acid as described in Example 25.

Examples 5 and 6:

For the preparation of hydroxamic acid, the activation of p-ammobenzenesulfonyl-Tic is carried out in the same manner as described in Example 13, except that double the amount of ethyl chloroformate and N-methylmorpholine is used. It is irreversible

N-Ethoxycarbonyleinung in one step with the activation of the carboxylic acid. Examples 7, 8 and 9:

The p- or m-aminobenzenesulfonyl-Tic described above is among the

Schotten-Baumann conditions known to those skilled in the art. The following are used for this: Example 7: salicylic acid chloride, example 8:

p-methoxybenzoic acid chloride, Example 9: benzyl chloroformate. The further conversion to hydroxamic acid is carried out as in Example 25

described.

Example 13:

R-2- (4-phenoxybenzenesulfonyl) -1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid

General working instructions:

Tic benzyl ester p-toluenesulfonate

1 mol of Tic (free amino acid), 10 mol of benzyl alcohol and 1 mol of p-toluenesulfonic acid monohydrate are dissolved or suspended in 1.2 l of toluene and heated under reflux on a water separator. After completing the

The solvent is evaporated off, the solid, crystalline residue is taken up several times in diethyl ether and suction filtered and then dried in an oil pump vacuum. Yield: quantitative

¹ H-NMR: (200 MHz, δ in ppm, DMSO-d ₆ ) 9, 7 (s, br., 2 H, prot. NH), 7, 5-7.25 (2m, 7H, aroma.) , 7, 1 (d, 2H, aroma p-TsOH), 5.3 (s, 2H, CH ₂ benzyl); 4.7 (dd, 1H, CHα); 4.4 "d", 2H, CH ₂ ); From 3.4 to 3, 1 (m, 2H, CH _2); 2.3 (s, 1H, CH ₃ p-TsOH).

Tic sulfonation

0.1 mol of Tic solution (free amino acid 1 7.7 g) in 50 ml of 2 N aqueous NaOH is mixed with finely powdered sulfonic acid chloride (105 mmol) at 0 ° C., followed by 14.2 g (110 mmol) of diisopropytethylamine and 50 ml acetone or THF. After 10 min, the ice bath is removed and the more or less homogeneous solution is stirred at RT for a further 6 h. The reaction mixture is then concentrated, 300 ml of ethyl acetate are added and the mixture is acidified with 4N HCl. The organic Phase is separated, the aqueous phase is extracted twice with 50 ml of ethyl acetate. The combined organic phases are shaken out with saturated NaCl solution and dried over sodium sulfate. After the solvent has been distilled off, the sulfonated remains

Tetrahydroisoquinoline carboxylic acid as an oily or solid residue, which in some cases can be purified by recrystallization from ethyl acetate / petroleum ether, but is often already sufficiently pure for further reaction.

1 3a R-2- (4-phenoxybenzenesulfonyl) -1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester

A solution of 1, 92 g (0.01 mol) of R-1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester and 2.7 g (0.01 mol) of 4-phenoxybenzenesulfonyl chloride in 50 ml of absolute THF are in the presence of 1.7 ml (0.01 mol) of N-ethylmorpholine heated under reflux for 8 h. After removing the

The residue is taken up in solvent in dichloromethane and extracted successively with 5% citric acid, 5% sodium bicarbonate solution and 2 × with water. Drying over sodium sulfate and concentrating the organic phase gives the ester, which is reacted further without purification. Yield: 4.0 g (95% of theory) of 1 3a.

1 3b R-2- (4-phenoxybenzenesulfonyl) -1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid

A solution of 4.0 g (9.5 mmol) of the ester (1 3a) in 50 ml of isopropanol is stirred for 24 hours at room temperature after the addition of 9.5 ml of 1N sodium hydroxide solution. The mixture is then acidified with 1N hydrochloric acid and the mixture is evaporated to dryness under reduced pressure. The residue is taken up in toluene, extracted with 5% citric acid and, after drying the organic phase over sodium sulfate, evaporated in vacuo.

Yield: 3.4 g of carboxylic acid 1 3b (83% of theory)

Melting point: 147 ° C 13c R-2- (4-phenoxybenzenesulfonyl) - 1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid

3.4 g (8.3 mmol) of the carboxylic acid 1 3b are dissolved in 30 ml of DMF and successively at -20 ° C. with 1.4 g (1 2 mmol) of N-ethylmorphohn and 1.13 g (8.3 mmol) isobutyl chloroformate added. After an activation time of 30 min, 4.37 g (41.5 mmol) of O-trimethylsilylhydroxylamine are added and stirring is continued for 4 h at RT. After adding 250 ml of ethyl acetate and 500 ml of water, it is acidified with citric acid. After separating the organic phase and shaking the aqueous phase 4 times, the combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. Recrystallization from toluene / ethyl acetate (1: 1) gives the

Title link 1 3.

Yield: 2.9 g (82% of theory) Melting point: 1 70 ° C (decomposition)

Example 1 7:

Trans-beta-styrene sulfonyl chloride is used for the sulfonation of the tic benzyl ester under standard conditions (see Example 1 3). In the

Subsequent hydrogenation (H2, Pd / C) takes place in one step Debenzyherung and hydrogenation of the double bond. Then hydroxamic acid formation analogous to Example 25.

Examples 20, 21 and 22:

The starting point is commercially available 7-hydroxy-tic. This is sulfonated under standard conditions analogous to process variant d). After the usual work-up, a mixture of 2- and 7-disulfonated and exclusively 2-sulfonated-7-hydroxy-tic is obtained. At this stage, however, it is not necessary to separate the two connections. Further conversion to hydroxamic acid takes place directly

Standard conditions. As expected, partial ethoxycarbonylation of the 7-hydroxy group occurs during activation. The hydroxamic acid product mixture therefore contains all three products by chromatography on silica gel 60, preparative thin layer chromatography or HPLC can be separated.

Example 23:

To represent the 7-nitro-tic is commercially available from enantiomerically pure

(R) -Tic-OH or (S) -Tic-OH assumed. According to E. D. Bergann, J. Am. Chem. Soc. 74, 4947 (1 952) or according to E. Erlenmever, A. Lipp, Liebigs Ann. Chem. 21 9, 218 (1983) prepared by nitration with nitrating acid.

A mixture of the 6- and 7-nitro isomers is formed, the reaction mixture also containing non-nitrated starting compound. Before the separation, sulfonation of the

Mixtures carried out under standard conditions. The mixture of the three sulfonamides obtained can now be chromatographed on silica gel 60. Mixed fractions are obtained in succession which contain educt / 6-nitro- and 6-nitro- / 7-nitro- (4-methoxybenzenesulfonyl) -tic; lastly, pure fractions of the

7-nitro compound eluted. As usual, this can be converted further to hydroxamic acid analogously to Example 25.

Example 24:

2- (4-methoxybenzenesulfonyl) -6,7-methylenedioxy-1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid

The preparation of the corresponding carboxylic acid benzyl ester from the

Carboxylic acid corresponds to the general working instructions (see example 13).

For sulfonation or benzyl ester cleavage, the procedure is analogous to Example 25a.

The free, sulfonated carboxylic acid is reacted as described under 25b.

The product is obtained in crystalline form after treatment with diethyl ether. Yield:

140 mg, 57% of theory Theory; Melting point 1 66 ° C. Example 25:

2- (4-methoxybenzenesulfonyl) -6,7,8-trimethoxy-1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid

25a 2- (4-methoxybenzenesulfonyl) -6,7,8-trimethoxy-1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid

The benzyl ester is prepared according to the general working instructions (see example 13). For sulfonation, 1.2 g (3.05 mmol) of

Benzyl ester used. This is dissolved in 20 ml of THF and 0.63 g (3.05 mmol) of 4-methoxybenzenesulfonyl chloride are added at 0 ° C. After the addition of 0.32 ml of N-methylmorpholine, the mixture is stirred at 0 ° C. to room temperature overnight. Then it is mixed with 20 ml of ethyl acetate and with 10 percent sodium carbonate solution and saturated NaCl solution

shaken out. The organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. The remaining residue is chromatographed on silica gel 60 with ethyl acetate / petrol ester / glacial acetic acid 20/10/1 under pressure. Pure product fractions (600 mg) are combined and, after concentration, hydrogenated directly with 100 mg 10% Pd / C in 50 ml ethanol. After the reaction has ended, the catalyst is separated off and the remaining solution is evaporated under reduced pressure. 330 mg (66% of theory) are obtained.

25b 2- (4-methoxybenzenesulfonyl) -6,7,8-trimethoxy-1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid

330 mg (0.75 mmol) of the carboxylic acid from Example 25a are dissolved in 15 ml of THF and successively at -20 ° C. with 0.07 ml (0.75 mmol) of ethyl chloroformate and 0.15 ml (1.5 mmol ) N-methylmorpholine (NMM) added. After 30 minutes at this temperature, 0.474 ml of O-trimethylsilylhydroxylamine (3.75 mmol) is added. After 6 h at RT, 30 ml of ethyl acetate are added and the mixture is shaken with 20 percent aqueous citric acid and saturated NaCl solution. After drying the organic phase over sodium sulfate and evaporation under reduced pressure leaves 290 mg of a light, viscous oil which becomes crystalline by treatment with diethyl ether.

Example 26:

2- (morpholinosulfonyl) -1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid

26a 2- (Morpholinosulfonyl) -1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester

To a solution of 4.8 g (0.025 mol) of 1,3,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester and 2.9 g (0.025 mol) of N-ethylmorpholine are added 4.2 g (0.025 mol) of morpholine with stirring. N-sulfonic acid chloride added dropwise in 20 ml of THF. After stirring at RT for 2 h, the reaction is heated to reflux after 2 h to complete. After treating the CHCl _3- enriched reaction solution with 5 percent citric acid, 5 percent NaHCO ₃ solution and water, the organic phase is dried over Na ₂ SO ₄ and concentrated to dryness. Yield of ester (26a): 7.5 g (92% of theory)

26b 2- (morpholinosulfonyl) -1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid reaction of 7.5 g (0.023 mol) 26a analogous to 13b.

Yield of carboxylic acid 26b: 6.7 g (93% of theory)

26c 2- (morpholinosulfonyl) -1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid 2.3 g (7.5 mmol) of the carboxylic acid 26b are dissolved in 40 ml of absolute THF and successively at -20 ° C. with 1, 2 g (1 2 mmol) of N-methylmorpholine and 1.1 g (7.5 mmol) of isobutyl chloroformate were added. After 30 min, 3.9 g (37.5 mmol) of O-trimethylsilylhydroxylamine are added and the mixture is stirred at RT for a further 5 h. After adding 200 ml of water, it is acidified with dilute HCL and shaken out several times with dichloromethane. The collected organic phases are dried over Na ₂ SO ₄ and evaporated under reduced pressure. The oil obtained on Kieseigel 60 under pressure

Chromatograph ethyl acetate / dichloromethane (1: 1) as the mobile phase. Recrystallization of the product fractions from ethyl acetate gave crystalline

Hydroxamic acid 26c.

Yield: 1, 4 g (55% of theory) melting point: 1 64-1 65 ° C (decomposition)

Example 28:

1 - (4-methoxybenzenesulfonyl) indoline-2-hydroxamic acid

28a 1 - (4-methoxybenzenesulfonyl) indoline-2-carboxylic acid

1 g (6, 1 mmol) of indoline-2-carboxylic acid and 2.5 g (1 2.2 mmol) of 4-methoxybenzenesulfonyl chloride are at 50 ° C and 0.02 mbar for 4 hours (h) in a Kugelrohr with constant slow rotation leave. The brownish, crystalline product is then taken up in sodium carbonate solution and extracted twice with diethyl ether. The aqueous phase is acidified with 6N HCl and extracted four times with ethyl acetate. After being shaken out with saturated NaCl solution, the combined organic phases are dried over sodium sulfate and evaporated under reduced pressure. Remaining

Residual solvents are removed in an oil pump vacuum.

Yield: 1.34 g, (65% of theory)

¹ H NMR: (DMSO-d ₆ ) 7.8; 7.1 (2d, 4H, aroma p-TsOH); 7.4-7.0 (m, 4H, aroma); 4.9 (dd, 1H, CHα); 3.8 (2, 3H, OMe); 3.4 to 2.9 (2 dd, 2H, CH ₂₎

28b 1 - (4-methoxybenzenesulfonyl) indoline-2-hydroxamic acid

1.3 g (3.9 mmol) of 1 - (4-methoxybenzenesulfonyl) indoline-2-carboxylic acid according to Example 28a are dissolved in 10 ml of N, N-dimethylacetamide (DMA) and successively at -20 ° C. with 0. 37 ml (1 equivalent) of chloroformate and 0.81 ml of N-methylmorpholine were added. After an activation time of 30 minutes (min), 3.8 ml (19.5 mmol) of O-trimethylsilylhydroxylamine are added and stirring is continued for 4 h at RT. After diluting with

Ethyl acetate is acidified with citric acid and after

Separation of the aqueous phase washed with saturated NaCl solution. The organic phase is dried over sodium sulfate, filtered off and under evaporated under reduced pressure. The oil obtained is chromatographed on silica gel 60 under pressure using dichloromethane / ethyl acetate / acetic acid 5.5 / 3.5 / 1 as the mobile phase. Product fractions (with a positive iron-III-chloride reaction) are combined and evaporated. The crystalline product is then mixed with diethyl ether and freed from solvent residues under reduced pressure.

Yield: 400 mg (33% of theory). Melting point: 142 ° C

Example 29:

R-5- (4-methoxybenzenesulfonyl) -4, 5,6, 7-terahydro-1 H-imidazo- (4,5-c)

pyridine-6-hydroxamic acid hydrochloride

29a: R-3,5-di (4-methoxybenzenesulfonyl) -4,5,6,7-tetrahydro-1 H-imidazo (4,5-c) pyridine-6-carboxylic acid

To a solution of 6.1 g (30 mmol) of 4,5,6,7-tetrahydro-1 H-imidazo (4,5-c) pyridine-6-carboxylic acid hydrochloride in 50 ml of water are 1 in succession with ice cooling 5 ml of 2N NaOH and 4.5 g (42 mmol) of sodium carbonate were added. 1 3.7 g (67 mmol) is added with stirring

4-methoxybenzenesulfonyl chloride in 40 ml ether. After stirring for a further 24 hours at RT, the reaction mixture is adjusted to pH 3-4 with 5N HCl with ice cooling and extracted with ethyl acetate. After drying over sodium sulfate, filtering and concentrating to dryness, the organic phase gives 11.9 g (78% of theory) of the desired product in the form of an oil.

29 b: R-5- (4-methoxybenzenesulfonyl) -4, 5,6,7-tetrahydro-1 H-imidazo (4,5-c) pyridine-6-carboxylic acid hydrochloride

23.5 ml of 1N NaOH are added dropwise with stirring to a solution of 11.0 g (24 mmol) of disulphonated intermediate in 300 ml of methanol with ice cooling at intervals of 1 hour. After 6 hours, 1 5 ml of 1N-NaOH are finally added and stirring is continued at RT overnight. After removing the methanol in vacuo, the mixture with 5N-HCL adjusted to pH 5. The crystals which precipitate out are filtered off with suction and dried in vacuo over P205.

Yield: 5.2 g (60% of theory) on 29 b

Melting point: 264-265 ° C (decomp.)

29 c: R-5- (4-methoxybenzenesulfonyl) -4,5,6,7-tetrahydro-1 H-imidazo (4,5-c) pyridine-6-hydroxamic acid hydrochloride

8.0 g (24 mmol) of compound 29b in 60 ml of DMF are mixed with 4.27 g (24 mmol) of tetramethylammonium hydroxide and then at 0 ° C. with 2.7 g (24 mmol) of N-ethylmorpholine and in portions with 5.2 g (24 mmol) of di-tert-butyl dicarbonate added. After stirring overnight, the reaction mixture is poured onto ice water, adjusted to pH 5 with dilute HCl and several times with

Ethyl acetate shaken out. The combined, dried organic phase, after removal of the solvent, gives 10.5 g of BOC-protected 29b, which is used directly to prepare the hydroxamic acid.

For this purpose, 10.5 g (23 mmol) of the above compound is dissolved in 150 ml of absolute THF, and 4.4 g (38 mmol) of N-ethylmorpholine and 3.4 g (25 mmol) of isobutyl chloroformate are added at -20 ° C. After stirring for 1 hour, 10.9 g (0.1 mol) of O-trimethylsilylhydroxylamine are added, the temperature being kept at -20 ° C. over 1 hour. After stirring for a further 4 hours at RT, the reaction mixture is adjusted to pH = 1 with 1N HCl, 300 ml of water are added and the mixture is extracted several times with dichloromethane. The United

organic phases are dried over sodium sulfate and evaporated to dryness in vacuo.

To remove the BOC protective group, 8.1 g of the remaining oil are taken up in 50 ml of dichloromethane and 25 ml of trifluoroacetic acid are added dropwise at 0.degree. After 4 hours of stirring at RT, the reaction mixture is in

Vacuum concentrated. The residue is digested with dichloromethane, then dissolved in 0.1N HCl, filtered and freeze-dried.

Yield of hydroxamic acid 29 5.2 g (56% of theory)

Melting point. 1 10 ° C Example 31:

R-2- (4-methoxybenzenesulfonyl) -1,3,4,4-tetrahydro-9H-pyrido- (3,4-b) indole-3-hydroxamic acid

31a R-2- (4-methoxybenzenesulfonyl) -1, 2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid

A solution of 2.16 g (10 mmol) 1, 2,3,4-tetrahydro-9H-pyrido (3,4-b) -indole-3-carboxylic acid in a mixture of 10 ml acetone and 10 ml water after the addition of 10.5 ml of 2N NaOH, 2.06 g (10 mmol) of 4-methoxybenzenesulfonyl chloride were added with stirring. After stirring for 1 8 hours

After removal of the acetone, the solution is adjusted to pH = 1 with concentrated HCl at room temperature. The resulting precipitate is filtered off, washed with water and dried

Yield: 2.7 g of carboxylic acid 31 a (85% of theory)

Melting point: 232-234 ° C

31 b R-2- (4-methoxybenzenesulfonyl) -1, 2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-hydroxamic acid

2.5 g (7.4 mmol) of carboxylic acid 31 a are dissolved in 40 ml of absolute DMF and successively at -20 ° C with 1.4 ml (1 2 mmol) of N-ethylmorpholine and 0.97 ml (7.4 mmol) Isobutyl chloroformate added After a

Activation time of 30 min, 4.53 ml (37 mmol) of O-trimethylsilylhydroxylamine are added and the mixture is then stirred at room temperature for 19 hours. After the mixture has been adjusted to pH = 3.5 with citric acid, it is extracted several times with ethyl acetate. The combined organic phases are dried over sodium sulfate, concentrated under reduced pressure and chromatographically purified over silica gel with methylene chloride / methanol (95: 5). Yield: 2.4 g of hydroxamic acid (91.5% of theory)

Melting point: 87 ° C Example 32:

R-2- (4-phenoxybenzenesulfonyl) -1, 2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-hydroxamic acid

Production analogous to example 31

Melting point: 1 10-1 1 1 ° C

Example 33:

R-2- (4-morpholinobenzenesulfonyl) -1,3,4,4-tetrahydro-9H-pyrido (3,4-b) indole-3-hydroxamic acid

Production analogous to example 31

Melting point: 1 25 ° C (decomposition)

Example 42:

R-2- [4- (4-chlorophenoxy) benzenesulfonyl) - 1, 2,3,4-tetrahydro-isoquinoline-3-carboxylic acid

8.2 g (46.4 mmol) of R-1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid are mixed with 46.4 ml of 1N NaOH and 50 ml of acetone and brought to solution with water. 14.1 g (46.4 mmol) of 4- (4-chlorophenyloxy) benzenesulfonic acid chloride in 50 ml of THF are added dropwise at -5 ° C. with stirring, the reaction mixture being mixed with 6.0 g (46 , 4 mmol)

Dnsopropylethylamine is added. After stirring overnight, the

The precipitate is filtered off, the filtrate is adjusted to pH = 3 with 2N HCl and extracted several times with dichloromethane. The combined organic phases are, after drying over sodium sulfate, filtered and evaporated to dryness under reduced pressure. Recrystallization from toluene and drying under reduced pressure gives the title compound.

Yield: 1 6, 1 g (78% of theory) melting point 1 68-1 69 ° C.

NOT TO BE TAKEN INTO CONSIDERATION FOR THE PURPOSES OF INTERNATIONAL PROCESSING

Pharmacological examples

Representation and determination of the enzymatic activity of the catalytic domain of human stomelysin and neutrophil collagenase.

The two enzymes were prepared according to Ye et al., (Biochemistry 31 (1 992) 1 1 231 -5). To measure the enzyme activity or the enzyme inhibitor effect, 70 μl of buffer solution and 10 μl of enzyme solution with 10 μl of a 10% (v / v) aqueous dimethyl sulfoxide solution, which optionally contains the enzyme inhibitor, are incubated for 15 minutes. After adding 10 .mu.l of a 10% (v / v) aqueous dimethyl sulfoxide solution containing 1 mmol / l of the substrate, the enzyme reaction is monitored by fluorescence spectroscopy (328 nm (ex) / 393 nm (em)). The enzyme activity is shown as the increase in extinction / minute. The IC50 values listed in Table 3 were determined as those

Inhibitor concentration leading to 50% inhibition of the enzyme. The buffer solution contains 0.05 Brij (Sigma, Deisenhofen, Germany) and 0.1 mol / l Tris / HCl, 0.1 mol / l NaCl, 0.01 mol / l CaCl ₂ (pH = 7.5) for the Determination of the hydroxamic acids up to and including Example 33, or for the determination of the carboxylic acids from Example 34, 0.1 mo / l piperazine-N, N'-bis [2-ethanesulfonic acid] pH = 6.5.

The enzyme solution contains 5 μg / ml of one of the Ye et al. shown

Enzyme domains. The substrate solution contains 1 mmol / l of the fluorogenic

Substrates (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu-3- (2 ', 4'-dinitrophenyl) -L-2,3-diaminopropionyl-Ala-Arg-NH ₂ (Bachern, Heidelberg , Germany) .

2. Proteoglycan degradation assay

Principle of the assay:

In the proteoglycan degradation assay, the extent of cleavage of native, bovine aggrecan, the most important proteoglycan of the articular cartilage, measured. The released proteoglycan fragments are detected with the monoclonal antibody 5-D-4, which recognizes the keratin sulfate side chains that are carboxy-terminal at the G2 domain of the aggrecan. The assay thus primarily detects the pathologically significant cleavages that take place in the interglobular domain of the aggrecan.

After adding compounds of formula I and the enzyme in the form of the catalytic domain of stromelysin-1, the, after the cleavage

remaining amount of hyaluronic acid-bound aggrecan measured. The more aggrecan is detected, the lower the residual activity of the enzyme. The concentrations of compounds of the formula I at which the enzyme activity used (= 100% residual activity) is halved (= 50%

Residual activity) are shown by the IC50 values in Table 3

Description of the test procedure:

The wells of 96-well microtitre plates (Nunc, Maxisorp) are incubated with 100 μl hyaluronic acid solution (25 μg / ml hyaluronic acid (Sigma) in PBS) for 1 2 h at room temperature (RT) saturated with 100 ml of a 5% solution of bovine serum albumin (BSA), 0.05% Tween20 in PBS for 1 h at RT. The wells are then coated with proteoglycan by adding 100 µl of a solution of Bovinem to the wells

Nasal proteoglycan (ICI) (200 μg / ml in 1 × PBS, 5 mg / ml BSA, 0.05% Tween20) are incubated for 1 h at RT. Washing twice with 1 × PBS, 0.1% Tween20 removes the unbound proteoglycans. Then, for the actual assay, 60 ng of purified catalytic domain from

Stromelysin-1 (for recombinant expression and purification, see Ye et al (1,992) plus corresponding concentrations of inhibitor to be tested in 100 μl digestion buffer (100 mM MES pH 6.0, 100 mM NaCl, 10 mM CaCl ₂ , 0.05 % Brij) pipetted into the wells and incubated for 3 h at RT after twice Wash the wells with 1 x PBS, 0.1% Tween20 for 1 h at RT with 100 μl solution of the detection antibody (monoclonal antibody clone 5-D-4 (ICI), immunoreactive with the keratan sulfate side chains of the proteoglycan, in the dilution 1: 1000 in 1 x PBS, 5 mg / ml BSA, 0.05% Tween20). After washing twice with 1 x PBS, 0.1% Tween20, the

Immunoreaction of the bound detection antibodies with 100 μl per well of detection antibody solution (goat anti mouse IgG, labeled with peroxidase (Dianova), diluted 1: 1000 in 1 x PBS, 5 mg / ml BSA, 0.05% Tween20) for 1 h at RT . After washing again twice (as above), the color reaction is initiated with 100 μl of 2 mg / ml ABTS, activated with H ₂ O ₂ . The reaction products are measured in the ELISA reader at a light wavelength of 405 mm. Table 4 shows the results.

Claims

Claims:

1 . Compound of formula

and / or an optionally stereoisomeric form of the compound of the formula I and / or a physiologically tolerable salt of the compound of the formula I, where in the case i)

R ¹ for

a) a radical of formula II

b) a radical of the formula

c) a radical of the formula IV

wherein Z is a residue of a heterocycle or substituted heterocycle, such as

1) pyrrole,

2) thiazole,

3) pyrazole,

4) pyridine 5) imide azole,

6) pyrrolidine,

7) piperidine,

8) thiophene,

9) oxazole,

10) isoxazole,

1 1) Morpholine or

1 2) piperazine,

d) naphthyl,

e) naphthyl, mono- or trisubstituted by R ² , or

f) a radical of the formula V

where o is the number 1 or 2, and one of the

Carbon atoms in the ring is optionally replaced by -O- or -S- means, and

Q as part of structural formula I.

1) for structural part VI

2) the structural part VII

3) for structural part VIII

4) the structural part IX

or

5) for the structural part X

where D is NR or S,

R ² for

1) phenyl or

2) Phenyl mono- to trisubstituted by

2.1 hydroxy,

2.2 -OR ¹⁰ , wherein R ¹⁰

1) (C ₁ -C ₆ ) alkyl,

2) (C ₃ -C ₆ ) cycloalkyl,

3) benzyl or

4) phenyl means

2.3 -COOH,

2.4 (C ₁ -C ₆ ) alkyl,

2.5 (C ₃ -C ₆ ) cycloalkyl-O- (C ₁ -C ₄ ) alkyl,

2.6 halogen,

2.7 -CN,

2.8 -NO ₂ ,

2.9 -CF ₃ ,

2.10 -OC (O) -R ¹⁰ and R ¹⁰ as defined above,

2.1 1 -OC (O) -phenyl, mono- or disubstituted by R ³ ,

2.1 2 -C (O) -OR ¹⁰ and R ¹⁰ as defined above,

2.1 3 methylenedioxo,

2.14 -C (O) -NR ^{1 1} R ^{1 2} , wherein

R ^{1 1} and R ^{1 2 may be the} same or different and

1) hydrogen atom,

2) (C ₁ -C ₄ ) alkyl or

3) benzyl or

4) R ^{1 1} and R ^{1 2} together with the N atom to which they are attached form a pyrrolidine, piperidine, morphoin or piperazine residue, or

2.1 5 -NR ^{1 3} R ^{1 4} , where R ¹³

Represents hydrogen atom or (C ₁ -C ₄ ) -alkyl and R ¹⁴ 1) represents hydrogen atom,

2) (C ₁ -C ₄ ) alkyl,

3) benzyl,

4) -C (O) -R ¹⁰ or

5) is -C (O) -OR ¹⁰ and R ^{10 is} as defined above,

R ³ and R ^{4 are the} same or different and

1) hydrogen atom,

2) (C ₁ -C ₅ ) alkyl,

3) (C ₁ -C ₅ ) alkoxy,

4) halogen, 5) hydroxy,

6) -OC (O) -R ¹⁰ and R ¹⁰ as defined above mean, or

7) R ³ and R ⁴ together form the radical -O-CH ₂ -O-,

R ⁵ for

a) hydrogen atom,

b) (C ₁ -C ₅ ) alkyl or

c) benzyl, and

R ⁶ , R ⁷ and R ^{8 are the} same or different and are for

a) hydrogen atom, or

b) have the meaning for case i) of R ² under points 2.1 to 2.14, and

n stands for zero, 1 or 2,

m stands for zero, 1 or 2, the sum of n and m being 1, 2 or 3, or

where in case ii)

R ¹ for

1) phenyl or

2) phenyl, mono- to trisubstituted by R ² , where R ^{2 is defined} as in case i) under points 2.1 to 2.1 5,

Q stands for the structural part X and

m means 1, or

where in case iii)

R ¹ , Q, R ⁶ , R ⁷ and R ^{8 are the} same or different and have the meaning given for case ii),

m and n are zero, 1 or 2 and the meaning of n and m is not the same, and

X for

a) a covalent bond,

b) -O-, c) -S-,

d) -S (OK

e) -S (O) ₂ -,

f) -C (O) - or

g) -C (OH) - stands, and

Y for

a) -O- or

b) -S- stands, and

A stands for HO-NH-C (O) - o or HO-C (O) - and

B is a) - (CH ₂ ) -, where q is zero, 1, 2, 3 or 4, or b) -CH = CH-.

2. A compound of formula I according to claim 1 and / or a physiologically acceptable salt of the compound of formula I and / or a

optionally stereosiomeric form of the compound of the formula I, where R ¹ in the case i) represents a radical of the formula II or III and Q represents the structural part VI, VII VIII or X,

R ¹ for case ii) represents phenyl or phenyl, mono- to trisubstituted by methoxy, and Q represents the structural part X, or

R ¹ for the case iii) for phenyl, Q for the structural part X, n is zero and m 2, and

A stands for HO-NH-C (O) - or HO-C (O) -,

B represents a covalent bond,

X represents oxygen atom or a covalent bond, and

R ² for phenyl or phenyl substituted by

a) hydroxy,

b) -OR ¹⁰ , in which R ^{10 is} (C ₁ -C ₃ ) -alkyl or benzyl, c) (C ₁ -C ₂ ) -alkyl, d) fluorine or chlorine,

e) -CN,

f) -CF ₃ or

g) NR ¹³ R ¹⁴ , wherein R ^{1 3} and R ^{14 are} (C ₁ -C ₃ ) alkyl, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} identical or different and for

a) hydrogen atom,

b) methoxy,

c) methylenedioxo,

d) amino or

e) Hydroxy stand.

3. A compound of formula I according to claims 1 or 2, wherein

R-2- (biphenylsulfonyl) -1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid, R-2- (4-chloro-biphenylsulfonyl) -1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,

R-2- (4-phenoxybenzenesulfonyl) - 1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,

R-2- (4-phenoxybenzenesulfonyl) - 1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

R-2- (4-dimethylaminobiphenylsulfonyl) -1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

R- - (4-methoxybenzenesulfonyl) -7-nitro-1, 2,3,4-tetrahydroisoquinoline-3-hydroxamic acid, 2- (4-methoxybenzenesulfonyl) -6,7-propylene-1, 2,3,4-tetrahydroisoquinoline-1-hydroxamic acid,

R-5- (4-methoxybenzenesulfonyl) -4,5,6,7-tetrahydro-1 H -imidazo- (4,5-c) -pyridine-6-hydroxamic acid,

R-2- (4-methoxybenzenesulfonyl) -1, 2,3,4-tetrahydro-9H-pyrido- (3,4-c) -indole-3-hydroxamic acid,

R-2- (4-phenoxybenzenesulfonyl) -1,3,4,4-tetrahydro-9H-pyrido- (3,4-c) -indole-3-hydroxamic acid is used.

4. A compound of formula I according to one or more of claims 1 to 3, characterized in that the central carbon atom between the amino and hydroxamic acid group is present as the R enantiomer.

5. A process for the preparation of the compound of formula I according to a

or more of claims 1 to 4, characterized in that a) an imino acid of the formula XI

wherein R ^{1 is} as defined in formula I and R _z denotes chlorine atom, imidazolyl or - OH, in the presence of a base to give a compound of the formula

XIV implements

wherein Q, R ¹ , n and m are as defined in formula I, or e) converting a compound of the formula XIV to a compound of the formula XV, or f) a compound of the process produced by process b) or c)

Formula XIV with the hydroxylamine of the formula XVI,

Splits off the oxygen protecting group, or g) a compound of the compound prepared by process d) or e)

Formula XV with the hydroxylamine of the formula XVI to give the compound of the formula I, or h) a compound of the formula I prepared by processes f) or g), which occurs in enantiomeric forms owing to its chemical structure, by salt formation with enantiomerically pure acids or Bases, chromatography on chiral stationary phases or derivatization by means of chiral enantiomerically pure compounds such as amino acids, separation of the diastereomers thus obtained, and cleavage of the chiral auxiliary group into the pure enantiomers, or i) the compound of the compound prepared by processes f), g) or h) Formula I either isolated in free form or, if acidic or basic groups are present, optionally converted into physiologically tolerable salts.

6. Medicaments containing an effective amount of at least one

A compound as claimed in one or more of claims 1 to 4 or as obtained as claimed in claim 5 and / or a physiologically tolerable salt of the compound of the formula I and / or a stereoisomeric form of the compound of the formula I, in addition to physiologically acceptable auxiliaries and Carriers, optionally other additives and / or other active ingredients.

7. Use of at least one compound of formula I according to one or more of claims 1 to 4, for the manufacture of medicaments for the prophylaxis and therapy of diseases, in the course of which an increased activity of matrix-degrading metalloproteinases is involved.

8. Use according to claim 7, for the treatment of diseases of the connective tissue such as collagenosis, periodontal diseases,

Wound healing disorders or chronic diseases of the musculoskeletal system such as inflammatory, immunological or metabolic acute and chronic arthritis, arthropathies, myalgias and disorders of bone metabolism or degenerative joint diseases such as osteoarthritis, spondylosis, cartilage loss after joint trauma or prolonged joint immobilization or ulceration or meniscus injury or bruising after meniscus or bruising or dermatitis or meniscus injury or dermatitis after meniscus or dermatitis or bruising after meniscus or dermatosis Atherosclerosis and stenosis or inhibition of tumor necrosis factor release or treatment of inflammation, cancer,

Tumor metastasis, cachexia, anorexia and septic shock.

9. A method for producing a medicament according to claim 6,

characterized in that at least one compound of the formula I according to one or more of claims 1 to 4 and / or at least one physiologically tolerable salt of the compound of the formula I and / or an optionally stereoisomeric form of the

Bring compound of formula I with physiologically acceptable excipients and carriers and optionally other additives and / or other active ingredients in a suitable dosage form.